P1306: CLINICAL AND GENOMIC ANALYSIS OF HIGH-GRADE TRANSFORMATION OF MARGINAL ZONE LYMPHOMA
Authors: C. Yannakou, D. Villa, C. Gould, Y. Kankanige, J. Lickiss, G. Ryland, S. Lade, G. Slack, W. Limvorapitak, C. Tam, J. Seymour, D. Westerman, P. Blombery
Journal: HemaSphere (2022)

Background: Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma with splenic, nodal and mucosa-associated (MALT) subtypes that may undergo high-grade transformation (tMZL). Aims: We aimed to describe the clinical features, treatment outcomes and genomic characteristics of tMZL. Methods: Patients with a diagnosis of tMZL managed at the Peter MacCallum Cancer Centre (PMCC) and the British Columbia Cancer Agency from 2002–2018 were identified from institutional databases. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tMZL tissue biopsies of >60% tumour burden. DNA sequencing was performed using the PMCC PanHaem hybridisation capture panel of genes recurrently mutated in haematological malignancy. Expression of immune-related genes was assessed using the NanoString nCounter® Immunology Panel (V2). Results: 43 patients with tMZL (21 males, median age 66 years (range 40-86), 74% advanced stage) were identified. MZL subtypes were: 12 splenic, 15 nodal and 16 MALT. 35% had tMZL at first presentation, the remainder had a median time from diagnosis to transformation of 54.5 months (range 3-270). 39 were diffuse large B-cell lymphoma (DLBCL), 1 was Hodgkin lymphoma (HL) and 3 were composite lymphomas (2 DLBCL/HL, 1 DLBCL/follicular lymphoma). Of the 26 cases in which cell of origin was assessed by immunohistochemistry 69% were non-GCB. First line treatment of tMZL was with anthracycline containing chemoimmunotherapy in 84% of cases. 40% of patients received consolidation with autologous stem cell transplantation. For the 41 patients treated intensively the complete remission rate to first line treatment was 80%. Median progression free survival and overall survival were 37 and 76 months respectively. DNA sequencing was performed in 25 cases. The most recurrent aberrations (>15% cases) involved genes involved in DNA damage repair, cell cycle regulation, Ras/Raf/MAPK signalling, epigenetic regulation, lymphocyte development/signalling, apoptosis and Notch signalling (Figure 1A). TP53 loss of function aberrations were detected in 24% of sequenced tMZL cases while genes involved in cell cycle regulation were mutated and/or deleted in 40%. Concurrent MYC and BCL2 translocations (evaluated in 26 cases) were detected by FISH and/or sequencing in only a single case (GCB origin). To evaluate the immune landscape of tMZL we performed targeted gene expression profiling. 23 tMZL were compared to 55 de novo DLBCL and 16 transformed follicular lymphoma (tFL) cases. Unsupervised clustering did not stratify cases by disease (tMZL/DLBCL/tFL) but did identify two distinct groups characterised by ‘hot’ and ‘cold’ tumour immune microenvironment (TIME) profiles. This dichotomy remained evident within tMZL when cases were stratified by disease (Figure 1B). When focussing on genes involved in the immune response, ‘hot’ tMZL samples were characterised by overexpression of genes related to immune cells, immune checkpoints and antigen presentation. The most upregulated genes in tMZL compared to de novo DLBCL were TNFRSF13 and CXCL13 (both logFC ≥2.0, p<0.05) while the most downregulated gene was FN1 (logFC -1.6, p=0.0057). When tMZL was compared to tFL the most upregulated genes were CCR6, TBX21 and IFNG (all logFC ≥1.7, p<0.05) while MME was the most downregulated (logFC -2.6, p=0.012). Image:Summary/Conclusion: We have described the clinical features, treatment outcomes and genomic characteristics of tMZL. Genomic data implicate TP53 and cell cycle dysregulation as contributors to the pathogenesis of tMZL, as is the case in tFL. ‘Hot’ and ‘cold’ tMZL TIME profiles were identified.